Understanding how an environmental stimulant affects cellular physiology to give rise to a specific phenotypic outcome is a fundamental step toward understanding development and pathogenesis. During development and in response to environmental insults, various signaling cascades culminate in the activation of key chromatin remodeling enzymes and transcription factors, which collectively modulate the chromatin architecture to establish and/or maintain gene expression programs controlling cell identity. Our laboratory uses integrative interdisciplinary approaches merging systems biology, functional genomics, and biochemistry to map, reconstruct, and characterize developmentally- and environmentally-responsive gene networks that control fundamental biological processes ranging from transcription and signal transduction to cellular response to changes in the environment. Specifically, we seek to understand how transcription regulators and epigenetic modifications regulate gene expression programs during cellular development and differentiation. To this end, we use embryonic stem cells (ESCs) as a model system. ESCs maintain a plastic yet stable program of self-renewal while allowing rapid induction of alternate gene expression programs to initiate differentiation. Despite the elucidation of many genes and pathways critical for the maintenance of the pluripotent state, the mechanisms that coordinate the activities of master regulators, key signaling pathways, and epigenetic features remain poorly understood, owing largely to incomplete characterization of the genetic network underlying ESCs. By integrating evidence from multiple omics datasets, we have identified several genes with previously unknown roles in ESC Biology. To understand the roles of these potential ESC regulators, we have been studying a select few to gain insights into their mechanistic roles in the maintenance of ESCs. Thus far, we have been successful in characterizing the roles of Nucleolin, and the NF-Y complex. We found that Nucleolin maintains ESC homeostasis by shielding against differentiation-inducing redox imbalance-induced oxidative stress, and the NF-Y complex facilitates chromatin accessibility for master ESC transcription factors. Collectively, these studies will provide a foundation for defining the mechanism and scope of novel ESC regulators within developmentally- and environmentally- responsive gene networks. As part of our ongoing efforts to better understand regulation of gene expression during early embryonic development, we have uncovered an unanticipated role for intragenic enhancers in attenuating their host gene expression. Using genetic deletions, we have demonstrated a physiological role for enhancer-mediated attenuation in cell-fate determination during early embryonic development. These findings illustrate, for the first time, that intragenic enhancers not only enhance transcription of one or more genes from a distance but also finetune transcription of their host gene through attenuation.